Discovery of <i>N</i>-Cyano-sulfoximineurea Derivatives as Potent and Orally Bioavailable NLRP3 Inflammasome Inhibitors
Sameer Agarwal, Santosh Sasane, Hardik Shah, Jignesh P. Pethani, Prashant Deshmukh, Vismit Vyas, Pravin S. Iyer, Harsh Bhavsar, Kasinath Viswanathan, Debdutta Bandyopadhyay, Poonam Giri, Jogeswar Mahapatra, Abhijit Chatterjee, Mukul R. Jain, Rajiv Sharma
Abstract
NLRP3 inflammasome mediated release of interleukin-1β (IL-1β) has been implicated in various diseases. In this study, rationally designed mimics of sulfonylurea moiety were investigated as NLRP3 inhibitors. Our results culminated into discovery of series of unprecedented N-cyano sulfoximineurea derivatives as potent NLRP3 inflammasome inhibitors. Compound 15 (IC50 = 7 nM) and analogues were found to be highly potent and selective NLRP3 inflammasome inhibitor with good pharmacokinetic profile. These effects translate in vivo, as 15, 29, and 34 significantly inhibit NLRP3 dependent IL-1β secretion in mice.